Non insulin dependent diabetes (NIDDM), a chronic illness affecting 6% of the US population, is characterized by increased hepatic glucose output (HGO), decreased peripheral glucose utilization and decreased insulin secretion. All three of these abnormalities are easily demonstrated in patients with hyperglycemia, but increased HGO is not generally seen in the prediabetic state when plasma glucose levels are minimally elevated. Factors responsible for the increase in HGO are poorly understood. Increased gluconeogenesis is observed in patients with NIDDM. However, studies performed in nondiabetic individuals have demonstrated that increased gluconeogenesis is associated with a compensatory reduction in glycogenolysis to prevent an increase in HGO. The investigators propose that it is the loss of this compensatory mechanism which leads to impaired glycogen storage and increased HGO in NIDDM. We also propose that the defect is acquired. The present proposal has been designed to examine this hypothesis by comparing the effect of increased gluconeogenesis on HGO in monozygotic twins discordant for NIDDM to nondiabetic control subjects. The defect in glycogen homeostasis appears to be reversible with fasting. Studies are planned to examine the effect of fasting on the disposition of glucose-6-phosphate derived from gluconeogenesis in diabetic and nondiabetic subjects. A likely site for the defect in hepatic glycogen homeostasis leading to increased HGO is glucose-6-phosphatase (G6Pase), a key enzyme in the net release of glucose from the liver. Using a cDNA to G6Pase, studies are planned to examine, for the first time in man, G6Pase gene expression in obese diabetic and nondiabetic subjects undergoing gastric bypass surgery after extensive preoperative metabolic characterization. A role for insulin in the regulation of G6Pase gene expression will be examined by the use of diazoxide, which is known to inhibit insulin secretion in man. Based on the novel observation that etomoxir (an inhibitor of FFA oxidation) inhibits G6Pase gene expression in nondiabetic animals, studies are described to examine the role of FFA on G6Pase gene expression and enzyme activity in vivo.